Maternal FMR1 premutation covariates correlate with intergenerational expansion and neuropsychiatric conditions

Background Maternal FMR1 CGG repeat size, AGG interruptions and age are established predictors of intergenerational expansion from premutation (PM) to full mutation (FM). Whether somatic CGG repeat instability provides additional predictive value remains unclear. We evaluate a multidimensional model integrating repeat structure, maternal age, somatic instability and FMR1 mRNA expression to predict transmission risk and maternal neuropsychiatric outcomes. Methods CGG repeat sizing, AGG interruptions and somatic instability were determined by PCR and capillary electrophoresis. FMR1 mRNA levels were quantified by quantitative real-time PCR. Psychiatric diagnoses were determined using the SCID-5, and anxiety and depression symptoms were evaluated with the SCL-90-R. Generalised estimating equations modelled FM transmission risk, and regression analyses evaluated associations with psychiatric outcomes. Results A total of 236 PM mothers and 323 offspring (276 FM, 47 PM) were included in this study. Maternal CGG repeat length (p<0.001) and maternal age at childbirth (p<0.001) independently increased the odds of FM transmission, whereas the presence of one (p=0.047) or two AGG interruptions (p<0.001) significantly reduced risk. Somatic instability was also independently associated with transmission outcome (p=0.046). FMR1 mRNA levels were associated with depressive disorders (p=0.018), and CGG repeat length was associated with increased depressive symptom severity (p=0.005). A greater proportion of expanded alleles was associated with decreased anxiety and depressive symptom severity with p=0.029 for both analyses but was not with instability. Conclusions Somatic instability contributes independent predictive information beyond CGG repeat length, AGG interruptions and maternal age for FM transmission risk and is associated with neuropsychiatric outcomes in PM carrier mothers.